Serotonergic Modulation of Brain Development: Genetic and Pharmacologic Influenc

大脑发育的血清素调节：遗传和药理影响

• 批准号: 7939339
• 负责人: JAY A GINGRICH
• 金额: $ 200万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939339
• 关键词: Serotonergic; Modulation; Brain; Development; Genetic

DESCRIPTION (provided by applicant): The current application proposes to create a Silvio O. Conte Center for Basic and Translational Mental Health Research to address the role of serotonin (5HT) signaling in brain development. Before 5HT assumes its canonical role as a neurotransmitter, it acts during early stages of neural growth to exert profound effects on brain structure and function. The Center hypothesizes that two modulators of developmental 5HT signaling include: genetic variants and serotonin selective reuptake inhibitors (SSRIs). In the first case, naturally occurring serotonergic polymorphisms are associated with measurable differences in human brain structure and function. In the second case, the fetus receives incidental exposure from maternal use of SSRI medications. Based on animal models and human imaging, the effects of augmented 5HT signaling on brain development may increase vulnerability to mental disorders as a long-term consequence. The Center will investigate both sources of 5HT signaling modulation and hypothesizes that fetal SSRI exposure and 5HTergic genetic variants will produce convergent effects on brain structure, function, and consequently behavior. The Center includes 4 projects and 4 cores that integrate epidemiology, clinical, and animal models to address the central hypothesis. The Center studies ~11,000 children with in utero exposure to SSRIs by following mental and physical health problems through adolescence. A companion project studies newborns exposed to SSRIs in utero using multi-modal neuroimaging and EEG to assess brain structure and function at the earliest ages. The brain effects of early-life SSRI exposure is studied in mouse models using the same multi-modal imaging measures as well as microscopic analyses of cellular properties that may underlie imaging abnormalities. The Center reasons that the influence of genetic modulators of 5HT is likely encoded during early development. We test this hypothesis through genetically stratified newborns and fetal rhesus macaques, and examining genetics, brain imaging, and EEG in a unique, clinically characterized, population at high and low risk for depression. The Center studies of early-life 5HT signaling and brain development should lead to a better understanding of whether some mental disorders have their origins in development-a question highly relevant to the mission of NIMH. PUBLIC HEALTH RELEVANCE: Estimates suggest that >100,000 infants are exposed to SSRIs in utero each year in the U.S. Yet, virtually nothing is known about the effects of SSRIs on fetal brain or their long-term consequences. The role of serotonin in brain development is clearly established in other species and likely applied to humans as well. The proposed Center would address an important public health question about long-term effects of SSRIs on the fetus and provide better understanding of how serotonin can influence brain maturation and behavior.

描述（由申请人提供）：当前的申请提议创建一个Silvio O. Conte基础和转化心理健康研究中心，以解决5-羟色胺（5HT）信号在大脑发育中的作用。在5HT担任其作为神经递质的规范作用之前，它在神经生长的早期阶段起作用，对脑结构和功能产生深远的影响。该中心假设两个发育5HT信号的调节剂包括：遗传变异和5-羟色胺选择性再摄取抑制剂（SSRIS）。在第一种情况下，天然存在的血清素能多态性与人脑结构和功能的可测量差异有关。在第二种情况下，胎儿会因母体使用SSRI药物而受到偶然暴露。基于动物模型和人类成像，增强5HT信号传导对脑发育的影响可能会增加对精神障碍的脆弱性，这是长期后果。该中心将研究5HT信号调制的来源，并假设胎儿SSRI暴露和5HTRGIC遗传变异将对大脑结构，功能和因此行为产生收敛作用。该中心包括4个项目和4个核心，它们整合流行病学，临床和动物模型以解决中心假设。该中心研究通过青春期遵循心理和身体健康问题，在子宫内暴露于子宫内的儿童。一个伴侣项目使用多模式神经影像学和脑电图研究了在子宫内暴露于SSRI的新生儿，以评估最早的大脑结构和功能。在小鼠模型中使用相同的多模式成像指标以及对可能基于成像异常的细胞性质的显微镜分析研究了早期SSRI暴露的大脑效应。在早期开发过程中可能会编码5HT遗传调节剂的影响的中心原因。我们通过遗传分层的新生儿和胎儿鼠尾草猕猴来检验这一假设，并以独特的，临床表征的，抑郁症的高风险和低风险检查遗传学，脑成像和脑电图。对早期5HT信号传导和大脑发育的中心研究应更好地理解某些精神障碍是否起源于发展，这是一个与NIMH任务高度相关的问题。 公共卫生相关性：估计表明，在美国，> 100,000名婴儿在子宫内暴露于子宫内，但实际上，SSRI对胎儿大脑或其长期后果的影响几乎一无所知。 5-羟色胺在大脑发育中的作用显然在其他物种中确定，也可能应用于人类。拟议的中心将解决有关SSRI对胎儿的长期影响的重要公共卫生问题，并更好地了解5-羟色胺如何影响大脑的成熟和行为。